Multiple lines of evidence indicate that estrogens promote breast cancer, Selective estrogen receptor modulators (SERMs), such as tamoxifen are first-line drugs used as adjuvant therapy for preventing recurrences and reducing mortality in women with a history of breast cancer. More recently, SERMs are becoming increasingly popular for preventing cancer, since studies found that tamoxifen and raloxifene reduce the incidence of estrogen receptor positive breast tumors. Although the exact mechanism whereby SERMs prevent breast cancer is unknown, it is clear that SERMs interact directly with two known estrogen receptors, ER-alpha and ER-beta. Understanding the role of ER-alpha or ER-beta is critical for identifying more selective SERMs for the prevention and treatment of breast cancer. Our studies with MCF-7 cells indicate that ER-alpha mediates cell proliferation in response to estrogens. The role of ER-beta is breast cancer is unknown. Yet, our studies indicate that a large percentage of ER positive and ER negative tumors contain ER-beta. Furthermore, our results indicate that ER-beta inhibits the growth of breast tumors. The increased DNA synthesis caused by estradiol is inhibited by 50% in MCF-7 cells infected with an adenovirus that expresses ER-beta. High intake of plant estrogens (phytoestrogens) is associated with a low incidence of breast cancer, A key question is: Why do estrogens increase the risk of breast cancer, whereas phytoestrogens might decrease the risk of breast cancer? Our studies with isoflavones suggest that the divergent action of estrogens and phytoestrogens on breast cells may result from differences in their ability to trigger transcriptional functions of ER-alpha or ER-beta. Based on these studies, we have hypothesized that estrogens increase breast cancer by interacting with ER-alpha to stimulate cell proliferation, whereas phytoestrogens may prevent breast cancer by interacting with ER-beta. It is known that tamoxifen and raloxifene interact with both ERs non-selectively. We have hypothesized that herbs used in Traditional Chinese Medicine to prevent and treat breast cancer may contain natural SERMs that selectively interact with ER-alpha or ER-beta Our preliminary data with 71 herbs indicates that like, isoflavones, some Chinese herbs also possess estrogenic activity and interact selectively with ER-alpha or ER-beta The major goal of this application is identify Chinese herbs that selectively trigger ER-beta or block ER-alpha transcriptional pathways, because we hypothesize that these herbs will be less likely to elicit proliferative effects on breast cells, compared to estrogens. To accomplish this goal, we will determine the effects of the individual herbs on: (1) proliferation of breast cancer cells (2) transcriptional repression and activation by ER-alpha or ER-beta (2) binding to purified ER-alpha or ER-beta (3) recruitment of co-regulator proteins to ER-alpha or ER-beta and (4) expression of growth promoting genes. These studies have the potential to determine the molecular mechanism whereby herbs differentially interact with ER-alpha or ER-beta to regulate gene transcription and cell proliferation. This information can also provide a scientific basis to prioritize herbs for clinical trials evaluation for their ability to prevent and treat breast cancer.